Proposal for Tyrosine Kinase Inhibitors for Non Small Cell Lung Cancer

31 May 2012 Proposal for Tyrosine Kinase Inhibitors for Non Small Cell Lung Cancer PHARMAC is seeking feedback on a proposal to: fund gefitinib (Iressa) as a first line treatment for patients with locally advanced, or metastatic, unresectable, non-squamous Non Small Cell Lung Cancer (NSCLC) expressing activating mutations of EGFR tyrosine kinase through a provisional agreement with AstraZeneca Limited. amend the funding criteria for erlotinib (Tarceva) such that it would no longer be funded as a second line treatment option for patients with NSCLC disease known to be negative for activating mutations of EGFR tyrosine kinase. This proposal would require that patients with advanced non-squamous NSCLC undergo testing for the presence of activating mutations of EGFR tyrosine kinase in order to access funding for first or second line tyrosine kinase inhibitors. The proposal is consistent with advice from the Pharmacology and Therapeutics Advisory Committee (PTAC) and its Cancer Treatments Subcommittee. Overall, if implemented, the proposal is expected to increase the health gains for lung cancer patients from EGFR tyrosine kinase inhibitor treatments and be cost saving to the Combined Pharmaceutical Budget and cost saving to DHBs in the medium to longer term, taking into account the anticipated changes in patient treatment pathways and the costs to DHBs of providing EGFR testing for all patients with locally advanced, or metastatic, unresectable, non-squamous NSCLC. Further details of this proposal, including how to provide feedback and background information, can be found below and on the following pages. Feedback sought PHARMAC welcomes feedback on this proposal. To provide feedback, please submit it in writing by 5 pm Thursday, 14 June 2012 to: Jackie Evans Therapeutic Group Manager PHARMAC Email: jackie.evans@pharmac.govt.nz Fax: 04 460 4995 Post PO Box 10 254, Wellington 6143 All feedback received before the closing date will be considered by PHARMAC s Board (or Chief Executive acting under delegated authority) prior to making a decision on this proposal. A510350 - T12-636 Page 1 of 6

Details of the proposal In relation to gefitinib (Iressa): Iressa 250 mg tablets would be listed in Section B and in Part II of Section H of the Pharmaceutical Schedule from 1 August 2012. The following prices and subsidies would apply (all prices are ex-manufacturer and exclude GST): Brand Pharmaceutical Presentation Pack size Price and subsidy Iressa gefitinib tab 250 mg 30 $1,700.00 Iressa would be funded subject to Special Authority criteria as follows: Gefitinib - Retail Pharmacy Specialist - Special Authority Special Authority for Subsidy Initial application only from a relevant specialist or medical practitioner on the recommendation of a relevant specialist. Approvals valid for 4 months for applications meeting the following criteria: Either: 1. All of the following: 1.1 Patient has treatment naïve locally advanced, or metastatic, unresectable, non-squamous Non Small Cell Lung Cancer (NSCLC); and 1.2 There is documentation confirming that disease expresses activating mutations of EGFR tyrosine kinase; and 1.3 Gefitinib is to be given for a maximum of 3 months; or 2. The patient received gefitinib treatment prior to 1 August 2012 and radiological assessment (preferably including CT scan) indicates NSCLC has not progressed. Renewal application only from a relevant specialist or medical practitioner on the recommendation of a relevant specialist. Approvals valid for 6 months where radiological assessment (preferably including CT scan) indicates NSCLC has not progressed. Gefitinib would be listed on the National Preferred Medicine List (PML) from the date of its implementation (currently estimated to be 1 July 2013). Any restrictions in the PML applying to the prescribing and dispensing of gefitinib will be no more restrictive than those applying to the listing of gefitinib in Section B of the Pharmaceutical Schedule. Iressa would have subsidy and delisting protection until 1 January 2015. In relation to erlotinib hydrochloride (Tarceva): Erlotinib hydrochloride (Tarceva) 100mg and 150 mg tablets would remain listed in Section B and in Part II of Section H of the Pharmaceutical Schedule at the current prices and subsidies. Tarceva would remain subject to a confidential rebate which reduces the net price and subsidy paid by the Funder. Tarceva would maintain its current subsidy and delisting protection until 1 December 2013. A510350 - T12-636 Page 2 of 6

The Special Authority criteria applying to all presentations of Tarceva in Section B of the Pharmaceutical Schedule would be amended as follows from 1 January 2014 (additions in bold): Erlotinib hydrochloride - Retail Pharmacy Specialist - Special Authority Special Authority for Subsidy Initial application only from a relevant specialist or medical practitioner on the recommendation of a relevant specialist. Approvals valid for 4 months for applications meeting the following criteria: All of the following: 1 Patient has advanced, unresectable, Non Small Cell Lung Cancer (NSCLC); and 2 Patient has documented disease progression following treatment with first line platinum based ; and 3 Either: 3.1 All of the following 3.1.1 The patient has non-squamous NSCLC; and 3.1.2 Documentation confirming that disease expresses activating mutations of EGFR tyrosine kinase; and 3.1.3 The patient has not received prior treatment with gefitinib; or 3.2 Insufficient biopsy sample available to determine EGFR mutation status or precise histological type; and 4 Erlotinib is to be given for a maximum of 3 months. Renewal application only from a relevant specialist or medical practitioner on the recommendation of a relevant specialist. Approvals valid for 6 months where radiological assessment (preferably including CT scan) indicates NSCLC has not progressed. Background The Treatments Gefitinib (Iressa, AstraZeneca) and erlotinib (Tarceva, Roche) are both oral inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. In October 2010 PHARMAC funded erlotinib subject to Special Authority criteria for the second line treatment, after failure of first line platinum based, of patients with advanced, unresectable, NSCLC. Erlotinib has subsidy and delisting protection until 31 December 2013. Since erlotinib was funded the correlation between the presence of specific activating mutations in the tyrosine kinase domain of EGFR and increased activity of the EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, has become well established. Evidence demonstrates that, compared with standard platinum based, TKI treatment significantly improved progression free survival by around 3-4 months and quality of life in patients with advanced NSCLC expressing EGFR activating mutations. Conversely, patients without EGFR activating mutations treated with a TKI had a significantly shorter time to disease progression compared with standard platinum based, 1.5 months vs 5.8 months respectively. Gefitinib is registered for the first line treatment of patients with NSCLC expressing activating mutations of EGFR tyrosine kinase. However, erlotinib is not currently registered for first line use. This proposal does not prevent PHARMAC from considering in the future the funding erlotinib for first line treatment once it is registered in this setting. A510350 - T12-636 Page 3 of 6

Clinical Advice The funding of EGFR TKI s for NSCLC has been considered by PTAC and its Cancer Treatments Subcommittee (CaTSoP). In summary, they considered that activating mutations in EGFR Tyrosine Kinase were associated with increased activity of TKIs. Members considered that approximately 40% of non-squamous NSCLC would express EGFR mutations but that most squamous cell NSCLC would not express EGFR mutations and would therefore be unlikely to benefit from TKI treatment. PTAC and CaTSoP recommended that gefitinib be funded for the first line treatment of patients with locally advanced, or metastatic, unresectable, non-squamous NSCLC expressing activating mutations of EGFR tyrosine kinase with high priority. They also considered that the current funding criteria for erlotinib were no longer appropriate as they enabled erlotinib to be funded for some patients [those with EGFR negative disease] where it is very unlikely to be effective and for whom standard platinum based treatment would be more efficacious. They recommended that the criteria for erlotinib be amended as proposed with high priority. Relevant published PTAC and CaTSoP minutes can be found on PHARMAC s website at http://www.pharmac.govt.nz/2012/01/25 and http://www.pharmac.govt.nz/2012/04/20?q=gefitinib EGFR testing and Treatment Pathways We consider that approximately 2000 new patients per annum would be diagnosed with lung cancer, approximately one third of whom would present with advanced, unresectable, nonsquamous NSCLC. These patients would undergo EGFR mutation testing in order to determine appropriate funded treatment options. We consider that DHBs would provide EGFR mutation testing for these patients, either in-house or through a third party provider, and have included the estimated costs for such testing in our analysis of the proposal. Approximately half of these patients would test positive and be eligible for first line gefitinib treatment (approximately 240 patients per annum). Those patients whose disease progresses following first line gefitinib treatment would be expected to be treated with platinum-based treatment in the second line setting followed by palliative or best supportive care. Patients who choose not to be tested, or those whose disease is negative for EGFR mutations, would be expected to receive first line platinum-based treatment. Palliative or best supportive care is expected to be provided to those patients whose disease progresses. Patients with indeterminant EGFR results, or insufficient biopsy sample available for testing, would be expected to receive first line platinum-based treatment. Those patients whose disease progresses would remain eligible for erlotinib funding in the second line setting followed by palliative or best supportive care. The current and proposed treatment pathways for patients with advanced NSCLC are outlined in the two diagrams at the end of this letter. NHC work on EGFR testing PHARMAC note that the National Health Committee (NHC) has undertaken and will next week be publishing on its website a Rapid Review of EGFR testing in patients focusing on A510350 - T12-636 Page 4 of 6

clinical safety & effectiveness, value for money, feasibility of adoption in the system and societal and ethical considerations. The purpose of the NHC s work is to enable the NHC to recommend: 1) whether or not EGFR gene testing should be publicly funded to determine eligibility for TKIs in patients with NSCLC in New Zealand and if so, 2) how the service should be provided in the short to medium term. For further information on this work please contact the NHC nhc_info@nhc.govt.nz Financial Impact to DHBs Overall, if implemented, the proposal is expected to increase the health gains for lung cancer patients. The net effect of the proposal would be cost saving to the Combined Pharmaceuticals Budget (CPB) (NPV 5 years, 8%). The proposal would result in incremental costs to DHBs from providing EGFR testing, however, these costs would be more than offset by the savings to the CPB in the medium to long term. Current NSCLC Treatment Pathway Unresectable NSCLC Stage IIIb/IV Erlotinib Palliative Chemotherapy or Best Supportive Care A510350 - T12-636 Page 5 of 6

Proposed Treatment Pathway Unresectable NSCLC Stage IIIb/IV Non-Squamous NSCLC Squamous NSCLC EGFR mutation testing EGFR +ve EGFR status non determinable* EGFR -ve Gefitnib Erlotinib Palliative Chemotherapy or Best Supportive Care *result inconclusive or insufficient biopsy sample available A510350 - T12-636 Page 6 of 6